Diabetes represents one of the most serious health crises worldwide. It is estimated by the American Diabetes Association that one person is diagnosed with diabetes every 17 seconds, while the International Diabetes Federation states that one person dies every seven seconds from diabetes. Diabetes growth continues to skyrocket, with over 382 million cases worldwide, and according to the Centers of Disease Control, one out of every three Americans will have Type II diabetes by 2050. Replacement of deficient ? cells with human islets has proven successful in treating diabetes. Unfortunately, the high cost, unpredictable availability, and variable quality of human islets hinder wide spread application. Thus, an abundant supply of high-quality ?-like cells generated from human pluripotent stem cells (hPSCs) has tremendous implications for both therapeutic application and the development of drug discovery platforms. RMS has developed and marketed a novel in vitro differentiation kit (ProgenMix(r)) that combines a precise, stepwise combination of growth factors, to generate ?-like cells from hPSCs. RMS has been working with multiple major pharmaceutical companies, who have tried ProgenMix(r) to differentiate human induced pluripotent stem cells (hiPSCs) into pancreatic cells for use in drug discovery, toxicity and efficacy studies. One company concluded that the resultant cells are mature enough to conduct a mouse study to reverse diabetes in mice, a strong indication of the potential usefulness of pancreatic cells grown with RMS' techniques. Beyond their potential use in transplantation to treat diabetes, human ? cells are needed to test candidate therapies for efficacy and toxicity. The development of candidate therapies requires extensive preclinical efficacy and toxicity testing but traditional animal and cadaveric tissue models have been inadequate. The recent introduction of human induced pluripotent stem cell (hPSC)-derived differentiated cells for testing candidate compounds in preclinical efficacy and toxicity studies has led to the commercial availability of several differentiated human cell types. However, the conspicuous absence of a ? cell product remains as a significant barrier to determining whether candidate therapies exhibit ? cell toxicity or promote ? cell function. Hence, RMS' ProgenMix(r) protocol represents a significant advancement towards the use of ? cells in routine toxicity and efficacy testing of candidate therapies. This proposal will focus on testing 10 hiPSC lines for their abilit to differentiate into functional ?-like cells that exhibit significant glucose stimulated insulin secretion (GSIS). We expect to identify 3-5 hiPSC lines that repeatedly meet or exceed our release specifications for a ?-like cell product which will be made available to our customers for internal toxicity and efficacy testing. Thus, an outcome of the project will be a database or compendium of phenotypic and functional data related to the variability of pancreatic lineage and ?-like cell differentiation from a variety of hiPSCs. The hiPSCs selected for the proposed studies will be only those that have a clear commercialization pathway allowing RMS to distribute ?-like cells to commercial and non-commercial organizations.